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Neuronal apoptosis and reversible motor deficit in dominant-negative GSK-3 conditional transgenic mice
Raquel Gómez-Sintes1, Félix Hernández, Analía Bortolozzi
1Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Madrid, Spain.
Abstract:
Increased glycogen synthase kinase-3 (GSK-3) activity is believed to contribute to the etiology of chronic disorders like Alzheimer's disease and diabetes, thus supporting therapeutic potential of GSK-3 inhibitors. However, sustained GSK-3 inhibition might induce tumorigenesis through beta-catenin-APC dysregulation. Besides, sustained in vivo inhibition by genetic means (constitutive knock-out mice) revealed unexpected embryonic lethality due to massive hepatocyte apoptosis. Here, we have generated transgenic mice with conditional (tetracycline system) expression of dominant-negative-GSK-3 as an alternative genetic approach to predict the outcome of chronic GSK-3 inhibition, either per se, or in combination with mouse models of disease. By choosing a postnatal neuron-specific promoter, here we specifically address the neurological consequences. Tet/DN-GSK-3 mice showed increased neuronal apoptosis and impaired motor coordination. Interestingly, DN-GSK-3 expression shut-down restored normal GSK-3 activity and re-established normal incidence of apoptosis and motor coordination. These results reveal the importance of intact GSK-3 activity for adult neuron viability and physiology and warn of potential neurological toxicity of GSK-3 pharmacological inhibition beyond physiological levels. Interestingly, the reversibility data also suggest that unwanted side effects are likely to revert if excessive GSK-3 inhibition is halted.
Insights
Inhibiting glycogen synthase kinase-3 (GSK-3) may harm adult neurons, causing apoptosis and motor deficits. However, halting inhibition can reverse these neurological side effects.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Glycogen synthase kinase-3 (GSK-3) activity is implicated in Alzheimer's disease and diabetes.
- Sustained GSK-3 inhibition may cause tumorigenesis and embryonic lethality due to hepatocyte apoptosis.
- Genetic inhibition of GSK-3 has shown severe adverse effects, necessitating safer therapeutic strategies.
Purpose of the Study:
- To investigate the neurological consequences of chronic GSK-3 inhibition using a conditional transgenic mouse model.
- To evaluate the therapeutic potential and potential toxicity of modulating GSK-3 activity in neurological contexts.
- To assess the reversibility of GSK-3 inhibition-induced side effects.
Main Methods:
- Generation of transgenic mice with tetracycline-inducible expression of dominant-negative GSK-3 (DN-GSK-3) under a neuron-specific promoter.
- Analysis of neuronal apoptosis, motor coordination, and GSK-3 activity in Tet/DN-GSK-3 mice.
- Assessment of the effects of halting DN-GSK-3 expression on neurological outcomes.
Main Results:
- Conditional GSK-3 inhibition in adult neurons led to increased apoptosis and impaired motor coordination.
- DN-GSK-3 expression caused reversible neurological deficits.
- Restoring normal GSK-3 activity normalized apoptosis and motor function.
Conclusions:
- Intact GSK-3 activity is crucial for adult neuron viability and physiological function.
- Pharmacological inhibition of GSK-3 beyond physiological levels may induce neurological toxicity.
- The reversibility of observed side effects suggests that halting excessive GSK-3 inhibition can mitigate harm.
